2-methyl-2-(tertiary alkyl cyclohexyl) pentan-4-ones and processes

ABSTRACT

NOVEL PRODUCTS PRODUCED BY THE PROCESS OF REDUCING BY MEANS OF HYDROGENATION A 2-METHYL-2-(4&#39;&#39;-ALKYLPHENYL)PENTAN-4-ONE AND THEN OXIDIZING THE RESULTING PRODUCT SO PRODUCED.

United States Patent Oflice 3,702,343 Patented Nov. 7, 1972 US. Cl. 260-586 B 1 Claim ABSTRACT OF THE DISCLOSURE Novel products produced by the process of reducing by means of hydrogenation a 2-methyl-2-(4-t-alkylphenyl)- pentan-4-one and then oxidizing the resulting product so produced.

BACKGROUND OF THE INVENTION There is a continuing search for materials having desirable fragrance properties. Such materials are sought either to replace costly natural materials or to provide new fragrances or perfume types which have not heretofore been available. Especially desirable qualities for substances having interesting fragrances are stability in a wide variety of perfumed articles and perfume compositions, ease of manufacture, and intensity of aroma.

The invention comprises the novel products, as well as the novel processes and steps of processes according to which such products are manufactured, the specific embodiments of which are described hereinafter by way of example and in accordance with which it is now preferred to practice the invention.

Briefly, the present invention provides novel 2-disubstituted pentan-4-one compounds; 2-methyl-2-(3'- and 4' talkyl cyclohexyl) pentan-4-ones having the formula:

CHiH O wherein one R is t-alkyl having 4 or 5 carbon atoms and the other R is H, and perfume and fragrance-modifying materials containing such ketones. The novel .ketones are obtained by novel processes involving oxidation of the corresponding secondary alcohols, as more fully described hereinafter.

It has been found that, unlike other substituted and unsubstituted cyclohexyl pentanones, such as those described in French Pat. 889,052 (published on Dec. 30, 1943) the ketones of this invention possess by themselves qualities associated with animal or physically attractive human body aromas having good intensity and persistence. This fragrance quality particularly adapts the novel ketones for incorporation into perfume compositions and fragrance-modifying compositions having a desirable chypre aroma or other aromas suitable for Modern French fantasy perfumes such as the chypre and aldehydey-bouquet types. The compounds of this invention will, when used in small percentages, add to the intensity and diffusion of the fragrance composition and alter the odor type so as to include an animal, sweaty, leathery note. It will be appreciated by those skilled in the art, from the present disclosure, that the fragrance character of the finished perfume compositions can be tailored to specific uses, as more fully described hereinafter.

Where R is t-butyl, the ketone has a boiling point of 70 C. at 4 mm. Hg pressure and a ri of 1.4557. The molecular weight indicated is 238, determined by mass spectroscopy.

A number of different starting materials can be utilized to produce the novel ketones.

REACTION SEQUENCE I In one method of this invention, 2-methyl-2-penten-4- one is reacted with benzene in the presence of a Friedel- Crafts catalyst to form 2-methyl-2-phenyl-pentan-4-one according to the procedure set forth in French Pat. 889,- 052 (published on Dec. 30, 1943). The 2-methyl-2-phenylpentan-4-one is then alkylated on the phenyl ring with a t-alkanol in the presence of a strong acid such as sulfuric acid or phosphoric acid to produce the corresponding 2- methyl-2-(4-t-alkyl phenyl)pentan-4-one. The 2-methyl-2- (4'-t-alkyl phenyl)pentan-4-one is reduced, preferably by means of hydrogenation, at pressures of the order of atmospheres in the presence of a hydrogenation catalyst such as Raney nickel to produce 2-methyl-2-(4-t-alkyl cyclohexyl)pentan-4-ol. The 2-methyl-2-(4'-t-alkyl cyclohexyl)pentan-4-ol is then oxidized using a strong oxidizing agent, such as Jones reagent (a mixture of sodium dichromate and dilute sulfuric acid) to produce the compound 2-methyl-2-(4-t-alkyl cyclohexyl)pentan-4-one. Alternatively, a ketal of 2-methyl-2-(4-t-alkyl phenyl)pentan-4-one may be formed (e.g. by reaction with ethyl ortho formate or ethylene glycol in the presence of an acid catalyst.) The ketal may then be hydrogenated as set forth above, forming the corresponding ketal of 2- methyl-2-(4'-t-alkyl cyclohexyl)pentan-4-one; which is, in turn, hydrolyzed in aqueous mineral acid.

The reaction to prepare 2-methyl-2-phenyl-pentan-4- one is carried out preferably at atmospheric pressure and at low temperatures of the order of 10 C. up to +5 C. It is preferred to use an excess of benzene of the order of ZOO-400%. The reaction is carried out in the presence of a Friedel-Crafts catalyst, as for example, metal chlorides, such as aluminum chloride, zinc chloride, zinc bro mide, stannic chloride, and the like. At the completion of the reaction, the reaction mixture is preferably poured onto ice and worked up. Alkylation of the phenyl moiety is effected by means of reacting the phenyl pentanone with a t-alkanol in the presence of a strong acid, thereby forming a t-alkyl phenyl pentanone. Preferably, both the phenyl moiety and the carbonyl moiety of the resulting pentanone are reduced using hydrogen in the presence of a Raney nickel or a noble metal catalyst such as palladium, rhodium and the like. The resultant substituted t-alkyl cyclohexyl pentanol is then oxidized to the corresponding ketone using suitable oxidizing agents such as; a mixture of dilute sulfuric acid and sodium bichromate; or a silver or copper metal dehydrogenation agent; or a silver or copper metal dehydrogenation agent in the presence of oxygen; 01 a mixture of acetone and aluminum isopropoxide. After the oxidation is complete, the reaction mixture is neutralized and/ or filtered to remove the oxidation catalyst and can then be washed several times with such materials as saturated, aqueous solutions of potassium or sodium bicarbonate to purify it. The novel ketones are recovered from the reaction mixture by suitable techniques such as distillation, extraction, chromatographic techniques and the like. It has been found that fractional distillation under vacuum is a desirable way to obtain the pure ketones from the reaction mixture.

The instant Reaction Sequence I is summarized as foll I HzSOA ROH R- atertiary i alkanol I A R reducing agent wherein R is tertiary alkyl.

REACTION SEQUENCE II In another method, equally suitable, a 2-methyl-2-halopentan-4-one (preferably Z-methyl-Z-chloropentan-4-oue) is first prepared by reacting a hydrogen halide with 2-methyl-2-penten-4-one. The resulting 2-methyl-2-halopentan-4-one is then reacted with a t-alkyl benzene, pref erably t-butyl benzene or t-amyl benzene in the presence of a Friedel-Crafts catalyst such as aluminum chloride, and the like, to form a mixture of 2-methyl-2-(4'-t-alkylphenyl)pentan-4-one and 2-methyl-2-(3'-t-alkylphenyl) pentan-4-one. The 2-methyl-2-(3' and 4-t-alkylphenyl) pentan-4-ones can then be hydrogenated in admixture or can be separated, as by distillation or the like and then hydrogenated, at pressures of the order of 100 atmospheres in the presence of a hydrogenation catalyst to produce 2-methyl-2-(3 and/or 4'-t-alkylcyclohexyl)pentan-4- 01 which is, in turn, oxidized to produce the pentanones of this invention. The hydrogenation and subsequent oxidation reactions are carried out under substantially the same conditions in both of the foregoing process sequences.

In a preferred process, the reaction to produce the Z-methyl-2-halopentan-4-one is carried out preferably at atmospheric pressure and at low temperatures of the order -30 C. up to 10 C. Use of pressures greater than atmospheric pressure enables the reaction to be carried out at higher temperatures; the requirement of the reaction being solubility of the gaseous hydrogen halide dissolving in the reaction mass. The reaction of the Z-methyl- 2-pentan-4-one (mesityl oxide) with the hydrogen halide is substantially instantaneous.

The hydrogen halides useful for this reaction, and contemplated within the scope of this invention, are HBr and HCl, where HCl is preferred because of its cost, ease of handling and ready availability. The mole ratios of the reactants are preferably such that the hydrogen halide used is in a slight molar excess over the mesityl oxide.

The resulting crude 2-methyl-2-halopentan-4-one need not be purified, but may be directly reacted with t-butyl benzene or t-amyl benzene in the presence of a Friedel- Crafts catalyst, and preferably, in the presence of a nonreactive solvent-diluent or one less reactive than t-arnyl benzene to form the corresponding 2-methyl-2-(4'-t-alkyl phenyl)pentan-4-one. Preferably, the alkylation is carried out at atmospheric pressure and at relatively low temperatures of the order -10 C. up to C. Any suitable Friedel-Crafts catalyst can be used. Aluminum chloride is preferred because of its low cost and ready availability. Although either reactant can be used in excess, and thus also act as a solvent for the reaction, it is preferred to use a solvent in the reaction mass, desirably a hydrocarbon such as cyclohexane, benzene, toluene, xylene or the like. Benzene is the preferred solvent because of its low cost and its high vapor pressure which permits its ready removal from the reaction mass at the termination of the reaction. It is preferable that the mole ratio of the reactants be in substantially a 1:1 mole ratio, that the solvent to reactant mole ratio be about 1:2, and that the mole ratio of Friedel-Crafts catalyst to reactants be 1:1. At the termination of the reaction, the reaction mass is poured onto a crushed ice-aqueous HCl mixture. The resulting organic phase is washed with weak acid and water and the aqueous wash layers may, if desired, be re-extracted with a solvent such as benzene.

The organic phases are combined, the solvent stripped and the reaction product is purified by fractional distillation.

As in Reaction Sequence I, the resulting purified 2-methyl-2-(4'-t-alkyl phenyl)pentan-4-one is then hydrogenated to obtain 2-methyl 2 (4' t alkylcyclohexyl) pentan-4-ol which is oxidized to produce 2-methyl-2-(4'-talkylcyclohexyl)pentan-4-one.

Reaction Sequence II is summarized as follows:

enu

oxidizing agent 0 0 ll l OW wherein R is tertiary alkyl and X is chloro or bromo. The 2-methyl-2-(3 and 4'-t-butyl cyclohexyl)pentan-4-ones, 2-methyl-2-(4' t amyl cyclohexyl)pentan 4 one and 2-methyl-2-(3-t-amyl cyclohexyl)pentan-4-one produced according to this invention are olfactory agents and can be incorporated into a wide variety of compositions which when added thereto in small quantities of about one or two percent will be enhanced by their property of imparting additional intensity and diffusion to the fragrance. These materials bring to perfumery a new dimension in animal notes different from the existing materials now in use; namely, civet, musk, ambergris, and castoreum. The ketones can be added to perfume compositions in their pure forms or they can be added to mixtures of materials in fragrance-imparting compositions to provide a desired fragrance character to a finished perfume material. The perfume and fragrance compositions obtained according to this invention are suitable in a wide variety of perfumed articles and can also be used to enhance, modify or reinforce natural fragrance materials. It will thus be appreciated that the ketones and mixtures thereof of this invention are useful as olfactory agents and fragrances.

The term perfume composition is used herein to mean a mixture of compounds, including for example, natural oils, synthetic oils, alcohols, aldehydes, ketones, esters, lactones, and frequently hydrocarbons which are admixed so that the combined odors of the individual components produce a pleasant or desired fragrance. Such perfume compositions usually contain: (a) the main note or the bouquet or foundation-stone of the composition; (b) modifiers which round-off and accompany the main note; (c) fixatives which include odorous substances which lend a particular note to the perfume throughout all stages of evaporation, and substances which retard evaporation; and (d) top-notes which are usually low-boiling, freshsmelling materials. Such perfume compositions or the novel materials of this invention can be used in conjunction with carriers, vehicles, solvents, dispersants, emulsifiers, surface-active agents, aerosol propellants, and the like.

-In perfume compositions the individual components contribute their particular olfactory characteristics, but the overall effect of the perfume composition will be the sum of the effect of each ingredient. Thus, the ketones of this invention can be used to alter the aroma characteristics of a perfume composition, for example, by highlighting or moderating the olfactory reaction contributed by another ingredient of the composition.

The amount of one or more ketones of this invention which will be effective in perfume compositions depends on many factors, including the other ingredients, their amounts and the effects which are desired. It has been found that perfume compositions containing as little as 1.0% by weight of the compounds of this invention, or even less can be used to intensify or augment and enhance various types of fragrance compounds, the odors of which may be desired to be imparted to colognes, perfumes, bath oils and other cosmetic products. The amount employed will depend on considerations of cost, nature of the end product, the effect desired in the finished product, and the particular fragrance sought. Higher concentrations of ketone will intensify the animal, sweaty, leathery note of the compositions.

The ketones disclosed herein can be used alone, in a fragrance-modifying composition, or in a perfume composition as an alfactory component in perfumes; colognes; bath preparations, such as bath oils and bath salts, and the like. When the ketones of this invention are used in finished perfumed articles, such as the foregoing, they can be used in amounts of 0.04% or lower. Generally, it is preferred not to use an excess of 2% of the compound of the invention in the perfumed oil, since the use of too much will tend to unbalance the total aroma and will needlessly raise the cost of the article.

The following examples serve to illustrate embodiments of the invention as it is now preferred to practice it. It will be understood that these examples are illustrative and the invention is to be considered restricted thereto only as indicated in the appended claims.

EXAMPLE I (a) Preparation of 2-methyI-Z-phenyl-pentan-4-one A mixture of: 624 g. (8 moles) of benzene and 196 g. (2 moles) of mesityl oxide are saturated at -3 C. to +1 C. with 109 g. of gaseous HCl.

In the course of 1 hour, 294 g. (2.2 moles) of aluminum chloride are added in portions of 22 g. at 4-9" C. Stirring is continued for 2 hours at -15" C. The reaction mixture is poured onto ice. The phases are separated, and the organic phase is washed three times with one volume of saturated sodium bicarbonate and twice with one equal volume of water. The organic phase is then dried over anhydrous magnesium sulfate. After flash distillation, the product is fractionated under vacuum.

(Yield: 83% of theory). Boiling point: 88 C. at 2 mm. Hg; n =1.5100.

(b) Preparation of 2-methyl-2-(4-t-butylphenyl)- pentan-4-one 528 g. (3 moles) of 2-methyl-2-phenyl-pentan-4-one produced by the foregoing process are added at 5-10 C. to 1200 g. of 93% sulfuric acid. The mixture is stirred and heated to 29 C. At 293l C. 289 g. (3.9 moles) of tertiary butyl alcohol are added to the stirred mixture over a period of 1 hour. Stirring is continued at the same temperature for 30 minutes and the reaction product is poured onto ice. The phases are separated and the organic phase is washed three times with one volume of saturated sodium bicarbonate and twice with one equal volume of water. The organic phase is then dried over anhydrous magnesium sulfate. Flash distillation is followed by fractionation under vacuum to provide a product having a boiling point 122123 C. at 2.5 mm. Hg and n =1.5038.

Use of tertiary amyl alcohol in the same proportion as the tertiary butanol was used, and using the same procedure as above, yielded 2-methyl-2-(4-t-amyl phenyl)pentan-4-one.

(c) Preparation of 2-methyl-2-(4-t-butylcyclohexyl) pentan-4-ol 148 g. (0.64 moles) of 2-methyl-2-(4-butyl phenyl) penta-4-one (produced by the process of Example I (b) or II(b)), g. of Raney nickel and 182 ml. of isopropanol are mixed in an autoclave at C. in the presence of hydrogen at a pressure of 1800 p.s.i. for a period of 4 hours. The yield of crude product is 94-95% at the end of this period. The crude product is fractionally distilled: Boiling point 126-128 C. at 2.5 mm. Hg pressure; n =1.4778.

Use of the 2-methyl-2-(4'-t-amyl phenyl)pentan-4-one yielded 2-methyl- 2- (4'-t-amyl cyclohexyl) penta-4-ol, using the above procedure. Use of 2-methyl-2-(3'- -'butyl phenyl)pentanl-one produced using the procedure of Example II (b) yielded 2-methyl-2-(3-t-butyl cyclohexyl)pentan-4-ol, using the above procedure.

(d) Preparation of 2-methyl-2-(4-t-butylcyclohexyl) pentan-4-one 237 g. (1.14 moles) of 50% sulfuric acid are added in 1 hour at 65-70 C. to a stirred mixture of 142 g. (0.59 mole) of 2-methyl-2-(4-t-butylcyclohexyl)pentan- 4-ol and a solution of 74.5 g. (0.25 mole) of sodium dichromate in 220 g. of water. Stirring is continued for 2 hours at 70 C. The reaction product is then poured onto ice. The phases are separated, and the organic phase is washed three times with one volume of saturated sodium bicarbonate and twice with an equal volume of water. The organic phase is dried over anhydrous magnesium sulfate and fractionated in vacuo. Yield: 90.4% of theory; boiling point:70 C. at 4 mm. Hg pressure; n :1.4557. Carbonyl content by oxidation=99.5%. The odor of the product is described as having an animal, sweaty, leathery note and physically attractive body odor.

Use of the 2-methyl-2-(4-t-amyl cyclohexyl)pentan-4- 01 as a starting material, in the same proportions and under the same conditions yields 2-methyl-2-(4'-t-amyl cyclohexyl)pentan-4-one. Use of the 2-methyl-2-(3-tbutyl cyclohexyl)pentan-4-ol as a starting material, in the same proportions and under the same conditions yields 2-methyl-2- 3-t-butyl cyclohexyl pentan-4-one.

EXAMPLE II (a) Prepajration of 2-methyl-2-chloropentan-4-one Into a 500 cc. flask, equipped with a stirrer, thermometer, and reflux condenser and gas-addition tube connected to a cylinder of hydrogen chloride, g. of mesityl oxide [2-methyl-2-pentan-4-one] are added. The mesityl oxide is cooled to a temperature between 10 C. and 0 C. and 66 g. of hydrogen chloride gas is bubbled into the mesityl oxide. When addition of the HCl is complete, the reaction mass is stirred for ten minutes at C. The 2-methyl-2-cloropentan-4-one weighing 240 g. is then removed from the reaction vessel for further use.

(b) Preparation of 2-methyl-2-(4'-t-butyl phenyl) pentan-4-one Into a 3-liter reaction vessel equipped with a stirrer, thermometer, reflux condenser and addition funnel, the following ingredients are added:

225 g. (1.67 moles): t-butyl benzene 135 g. (1.85 moles): anhydrous benzene 360 g. (2.72 moles): aluminum chloride The reactants are cooled to C. Over a period of thirty minutes, 240 g. of the crude 2-methyl-2-chloropentan-hone produced above are added, maintaining the temperature of the reaction mass at 10 C.0 C. Stirring is continued for 1 hour at C.

The reaction mixture is then poured onto a mixture of 1000 g. of crushed ice and 400 g. of concentrated hydrochloric acid. The mixture is stirred until all the ice has melted. The organic phase was then washed (a) with one-liter portions of 3% aqueous hydrochloric acid until neutral to Congo Red; then (b) three times with one-liter portions of water. The aqueous phase and aqueous washings were then combined and extracted with one liter of benzene.

The organic layers were then combined; and the henzene was distilled through a 22-inch packed column at 5 mm. Hg pressure and 3645 C. vapor temperature. The product, 2-methyl-2(4'-t-butyl phenyl) pentan-4-one in admixture with 2-methyl-2-(3-t-butyl phenyl)pentan- 4-one was then obtained by fractional distillation through the same distillation column at the following conditions:

Vapor temperature: 96133 C. Liquid temperature: 141-144 C. Pressure: 3.23.6 mm. Hg Reflux ratio: 20:1

The yield obtained was 53 g. The resulting phenyl pentanone mixture is then hydrogenated according to the procedure of Example I (c) and oxidized according to the procedure of Example I (d). The resulting Z-methyl- 2-(3' and 4't-butyl cyclohexyl)pentan-4-one mixture is found to have an animal, sweaty, leathery note and a physically attractive human body odor.

EXAMPLE III The following composition is prepared.

Ingredient: Parts by weight Santalol 60 Coumarin 70 Musk ketone 30 Musk ambrette 20 Ambreine BlbSOlUlZB 25 Tarragon oil 25 Angelica root oil 5 Clary sage Vetivert oil 60 Linalool 30 Patchouli oil 20 Iso-eugenol Methyl ionone Oakmoss absolute Bergamot oil 225 Jasmin absolute 20 Rose absolute 15 Methyl salicylate 2 Lavender oil 3 Vanillin 15 Heliotropin 35 Ylang oil, Manila Cinnamyl acetate 25 Parts by weight The original mixture was designed as a chypre essence. The addition of the pentan-4-one compound in the quantity given increases the intensity of the essence and increases the diifusion of the fragrance. The final odor had the same fresh, chypre note and the same all over odor balance, but in addition, had a kind of body odor to a pleasant degree.

When the compound Z-methyl 2 (4 tbutyl cyclohexyl)pentan-4-one is replaced with 2-methyl-2-(4-tamyl cyclohexyl)pentan-4-or1e or 2-methyl-2-(3'-t-butyl cyclohexyl)pentan-4-one, or 2-methyl-2-(3'-t-amyl cyclohexyl)pentan-4-one or mixtures of one or more of these four ketones, the same results as mentioned above are obtained.

EXAMPLE IV The composition of Example III was incorporated in a cologne at the rate of 4% in ethanol; and into a handkerchief perfume at a rate of 20% (using ethanol). The ketones produced in Example I and II afford an increased intensity and diffusion to this finished chypre bouquet and, in addition, impart a kind of body odor to the handkerchief perfume and cologne to a pleasant degree.

It will be appreciated from the present description that the novel ketones can be included in other perfume composition and in other perfumed articles.

What is claimed is: 1. The product produced by the process which comprises the steps of:

(A) reducing, by means of hydrogenation at a pressure of about atmospheres in the presence of a hydrogenation catalyst selected from the group consisting of Raney nickel, palladium and rhodium, a 2-methyl-2-(4'-t-alkyl phenyl)-pentan-4-one to obtain a 2-methyl-2-(4-t-alkyl cyclohexyl)-pentan-4 01; and

(B) oxidizing the said 2-methyl-2-(4'-t-al kyl cyclohexyl)-pentan- 4- ol thus produced using an oxidizing agent selected from the group consisting of (1) a mixture of dilute sulfuric acid and sodium bichromate; (2) silver; (3) copper; (4) oxygen in the presence of silver; (5) oxygen in the presence of copper; and (6) a mixture of acetone and aluminum isopropoxide, and

(C) recovering the resulting product, said t-alkyl moiety being selected from the group consisting of t-butyl and tamyl.

References Cited UNITED STATES PATENTS OTHER REFERENCES Krasilnikova et a1., Chem. Abstracts, vol. 69, p.

I.F.F., Chem. Abstracts, vol. 64, p. 20176, 1966.

Byers, Chem. Abstracts, vol. 41, p. 4614f, 1947.

Noller, Chemistry of Orgnaic Compounds, third edition, pp. 470-1 (1965).

BERNARD HELFIN, Primary Examiner N. MORG'E'NSTERN, Assistant Examiner US. Cl. X.R. 

